SUMMARY Since the times of Sir William Bayliss and Ernest Starling at the turn of the 20th century, the gut and the brain were thought to exchange sensory information only indirectly, through hormones. Using modern molecular tools, we recently uncovered a gut neuroepithelial circuit?analogous to that of taste cells in the tongue?formed by the innervation of sensory enteroendocrine cells. This peripheral neural circuit raise the possibility of understanding visceral hypersensitivity at the cellular level?a core symptom of several human disorders, including irritable bowel syndrome, chronic abdominal pain, and eating disorders. Enteroendocrine cells receive sensory stimuli from nutrients and bacteria in the gut lumen and respond by firing action potentials. Thus, this neuroepithelial suggests a path for gut sensory signals to modulate brain function and a receptacle for the brain to modulate gastrointestinal sensitivity. We formed an interdisciplinary team, with expertise in gut sensory neurobiology, biomedical engineering, and clinical gastroenterology, to define the brain-to-gut efferent function of this neuroepithelial circuit by taking advantage of newly developed animal models and in vivo technology. The focus on gastrointestinal chemosensory signaling has been afferent gut-to-brain pathways but the brain-to-gut efferent paths that modulate gastrointestinal sensitivity have been poorly described at best. In this Limited Competition - SPARC OT2 proposal, we focus on the efferent portion to produce foundational knowledge for future comprehensive mapping studies. We will pursue the following aims: 1. To map the vagal innervation of enteroendocrine cells in the small intestine. 2. To define the vagal modulation of the neuroepithelial circuit in vivo. By functionally mapping it, we envision developing a platform for future neuromodulation and dietary therapies to alleviate disorders of visceral sensory dysfunction.